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Doctoral Thesis
DOI
10.11606/T.42.2019.tde-16102018-120421
Document
Author
Full name
Louise Faggionato Kimura Vieira
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Picolo, Gisele (President)
Camarini, Rosana
Fonoff, Erich Talamoni
Munhoz, Carolina Demarchi
Parada, Carlos Amilcar
Title in Portuguese
Efeitos do enriquecimento ambiental na neuropatia periférica induzida em ratos.
Keywords in Portuguese
Analgesia
Dor neuropática
Enriquecimento ambiental
Macrófagos
Opioides endógenos
Abstract in Portuguese
O enriquecimento ambiental (EA) é capaz de alterar a percepção a estímulos nociceptivos, bem como de aumentar a resposta analgésica induzida por opioides. Considerando que a dor neuropática é um grave problema de saúde pública e o tratamento para esta condição ainda é insatisfatório e acarreta efeitos adversos severos, os objetivos deste trabalho foram avaliar a interferência do bem-estar animal na sensibilidade dolorosa de ratos frente a diferentes estímulos nociceptivos e investigar possíveis mecanismos envolvidos neste efeito. Os animais foram submetidos à avaliação da ansiedade e da sensibilidade dolorosa, em modelo de neuropática, frente a estímulos nociceptivos mecânicos e térmicos. Foi verificado que um protocolo de EA elaborado e iniciado desde o nascimento foi capaz de reverter totalmente a dor neuropática de animais submetidos à constrição crônica do nervo isquiático (CCI). Este efeito foi completamente abolido quando os animais enriquecidos foram tratados com naloxona, um antagonista opioide não seletivo. Análises de Western Blot não mostraram diferenças na expressão de receptores opioides em regiões relacionadas ao processamento e controle da dor, porém os níveis circulantes de beta-endorfina e met-encefalina aumentaram na presença de dor crônica nos animais enriquecidos. Os níveis séricos de corticosterona também se apresentaram aumentados nos animais com EA, independentemente da neuropatia, mas o tratamento com mifepristona, um antagonista de receptores de glicocorticoides, não alterou a analgesia dos animais operados. Ainda, o EA também reduziu a imunorreatividade para serotonina na medula espinal de animais com CCI. Além do efeito analgésico, o EA também reduziu o marcador de lesão neuronal ATF-3 no gânglio da raiz dorsal e, no local da constrição, reduziu a degeneração neuronal característica do modelo, induzindo ainda, a presença predominantemente de macrófagos do tipo M2. Este trabalho reforça a importância do bem-estar na prevenção do desenvolvimento da dor neuropática e mostra uma abordagem não farmacológica que pode aumentar a resiliência de animais contra estímulos nocivos.
Title in English
Effects of environmental enrichment on peripheral neuropathy induced in rats.
Keywords in English
Analgesia
Endogenous opioids
Environmental enrichment
Macrophages
Neuropathic pain
Abstract in English
Environmental enrichment (EE) is capable of altering the perception of nociceptive stimuli, as well as increasing the analgesic response induced by opioids. Considering that neuropathic pain is a serious public health problem and the treatment for this condition is still unsatisfactory and induces severe side effects, the aims of this study were to evaluate the interference of animal welfare in the sensitivity to different nociceptive stimuli and to investigate possible mechanisms involved in this effect. Animals were submitted to the evaluation of anxiety and pain sensitivity in a model of neuropathic pain, against mechanical and thermal nociceptive stimuli. It was seen that an elaborated EE starting from birth was able to totally reverse the neuropathic pain of animals submitted to chronic constriction injury of the sciatic nerve (CCI). This effect was completely abolished when enriched animals were treated with naloxone, a nonselective opioid antagonist. Western blot analysis did not show differences in opioid receptor expression in regions related to pain processing and control, however, circulating levels of beta-endorphin and met-enkephalin were increased in the presence of chronic pain in enriched animals. Serum corticosterone levels were also increased in animals with EE regardless of neuropathy, but treatment with mifepristone, a nonselective glucocorticoid receptor antagonist, did not alter the analgesia of operated animals. Moreover, EE reduced serotonin immunoreactivity in the spinal cord of CCI animals. In addition to analgesic effect, EE also reduced the neuronal injury marker ATF-3 at the dorsal root ganglia and, at the site of constriction, decreased the neuronal degeneration characteristic of the model, inducing the presence of M2 macrophages subtype predominantly. This work reinforces the importance of well-being in preventing the development of neuropathic pain and shows a non-pharmacological approach that may increase animal resilience against noxious stimuli.
 
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Release Date
2020-10-15
Publishing Date
2019-01-31
 
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